PRACTICE AID A Profile of the Progress With Targeted Therapy in AML

This Practice Aid has been provided as a quick reference to help learners apply the information to their daily practice and care of patients.

Approved and Emerging FLT3 and IDH1/2 Inhibitors in AML

FDA-approved FLT3 Inhibitors tests available to detect FLT3 mutations

FDA approved + CT in 50 mg orally twice daily Midostaurin1 FLT3-mutant AML with food Fast-track designation in 120-mg/d dose based Gilteritinib2 r/r AML; phase 3 on CHRYSALIS Quizartinib3 Phase 3 30-60 mg/d (r/r AML) 100 mg three times daily Crenolanib4 Phase 3 in early studies

GI events among the more common AEs noted with FLT3 inhibitors As with any oral medication, promote adherence to therapy Be mindful of potential drug–drug interactions (CYP3A4 inhibitors)

Detect IDH mutations IDH Inhibitors with RealTime™ IDH2 assay

FDA approved for r/r IDH2- Enasidenib (IDH2)5 100 mg orally daily mutation–positive AML Phase 3; expanded-access Ivosidenib (IDH1)6 program available; under 500 mg/d orally (phase 3) FDA review

FT-2102 (IDH1)7 Phase 1 TBD in ongoing trials

IDH2 inhibitors: Monitor for differentiation syndrome, GI events, elevated bilirubin5 PRACTICE AID A Profile of the Progress With Targeted Therapy in AML

Other Emerging Targeted Agents for AML

Therapies targeting Other Targeted Strategies Bcl-2, HhP, among others in development in AML

Bcl-2 inhibitor: venetoclax8 HhP inhibitor: glasdegib9

Phase 3 testing in AML “Breakthrough therapy” designation Phase 1/2 testing Dose in phase 3 trials: 400 mg orally 100-mg daily dose used in phase 2 daily in combination with combination studies low-dose cytarabine

Diarrhea, nausea, fatigue, Cytopenias and GI toxicity noted vomiting noted in studies in in early studies patients with AML

Major Phase 3 Trials of Targeted Agents in AML (Currently Enrolling Patients)

MORPHO Study Gilteritinib as maintenance → HCT in patients with NCT02927262 FLT3-mutation–positive AML Gilteritinib vs CT in r/r NCT02421939 FLT3-mutation–positive AML IDHENTIFY Study Enasidenib vs CCR in older patients with IDH-mutant NCT02577406 late-stage AML AGILE Study Ivosidenib vs placebo in combination with AZA in NCT03173248 previously untreated IDH1-positive AML Venetoclax + AZA vs AZA in treatment-naïve subjects NCT02993523 with AML ineligible for standard induction NCT02668653 Quizartinib + SoC CT and as maintenance in patients QuANTUM-First with newly diagnosed FLT3-ITD–positive AML

AML: acute myeloid leukemia; AZA: azacitidine; Bcl-2: B-cell lymphoma 2; CCR: conventional care regimen; CT: chemotherapy; CYP3A4: cytochrome P450 3A4; FLT3: fms-like tyrosine kinase 3; HhP: Hedgehog pathway; HCT: hematopoietic stem cell transplant; IDH: isocitrate dehydrogenase; ITD: internal tandem duplication; r/r: relapsed or refractory; SoC: standard of care. 1. Rydapt (midostaurin) Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/207997s000lbl.pdf. Accessed November 17, 2017. 2. Perl AE et al. Lancet Oncol. 2017;18:1061-1075. 3. Sandmaier BM et al. Am J Hematol. 2017 Nov 1 [Epub ahead of print]. 4. https://clinicaltrials.gov/ct2/show/NCT02298166. Accessed November 17, 2017. 5. Idhifa (enasidenib) Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209606s000lbl.pdf. Accessed November 17, 2017. 6. https://clinicaltrials.gov/ct2/show/NCT03173248. Accessed November 17, 2017. 7. https://clinicaltrials.gov/ct2/show/NCT02719574. Accessed November 17, 2017. 8. https://clinicaltrials.gov/ct2/show/NCT02993523. Accessed November 17, 2017. 9. Cortes JE et al. 58th Annual Meeting of the American Society of Hematology (ASH 2016). Abstract 99. Access the activity, “A Master Class on Building Better Therapy for AML: Making the Most of an Increasing Number of Innovative Options,” at www.peerview.com/MJN40. PRACTICE AID A Graphic Guide to Newer Cytotoxic and Antibody Strategies in AML

This Practice Aid has been provided as a quick reference to help learners apply the information to their daily practice and care of patients.

Summary of Recent Novel Cytotoxic Strategies Developed in AML

FDA approved in adults with newly Phase 3 studies completed diagnosed t-AML or AML-MRC Phase 2/3 studies ongoing

CPX-3511,2 Vosaroxin3,4

5:1 molar ratio of cytarabine First-in class anticancer to daunorubicin quinolone derivative Induction dose: daunorubicin 44 mg/m2 and cytarabine 100 mg/m2 IV over Dose used in phase 3 VALOR trial: 90 min, if needed 90 mg/m2 IV d 1 and 4 in first cycle; Consolidation: daunorubicin 29 mg/m2 and 70 mg/m2 in subsequent cycles cytarabine 65 mg/m2 liposome via IV over 90 min on d 1 and 3

Approval based on phase 3 data in older pts with newly diagnosed Phase 3 VALOR high-risk AML (N = 309): No differences in primary endpoint; CPX-351 improved % in secondary analysis, addition ü Median OS of vosaroxin to cytarabine improved OR ü Transplantation rate and CR in patients aged ≥60 y (N = 451) ü OS following HCT vs 7+3

When considering therapy: ü Monitor blood counts regularly Adverse events to note until recovery include stomatitis and sepsis (increased ü Not recommended in pts with with addition of vosaroxin in VALOR) cardiac function < normal PRACTICE AID A Graphic Guide to Newer Cytotoxic and Antibody Strategies in AML

In AML, diverse antibody technologies are approved for use or are being rapidly developed in phase 3 trials

Gemtuzumab ozogamicin CD33 225Ac-Lintuzumab AMG 330 (BiTE; CD33/CD3) Hu7007; SGN-CD123 CD123 Xmab (CD3/CD123) Multiple MGD006 IMGN632; IMGN779 antigen AML CD45 Iomab-B targets and cell agents CD47 Hu5F9-G4

CLL1 MCCLA-1117 (BiTE)

Current Status of Selected Antibody Technologies in AML

Antibody–Drug Conjugates Radioimmunoconjugates Gemtuzumab Vadastuximab 225Ac-Lintuzumab7 Iomab-B ozogamicin5 talirine6 ü Early-phase data + ü Anti-CD45 mAb ü FDA approved for ü Promising early LDAC in older combined with newly diagnosed activity patients with β particle CD33+ AML in ü Development r/r AML radionuclide 131I adults and r/r suspended ü Ongoing phase 2 ü Phase 2 data in pts CD33+ AML in (tolerability study continues aged >50 y with adults and in concerns in to enroll patients AML/high-risk MDS8 pediatric pts older patients) (as of October 2017; ü Phase 3 SIERRA aged ≥2 y NCT02575963) study currently ü Premedicate with enrolling pts corticosteroid, (NCT02665065) antihistamine, and acetaminophen

AML: acute myeloid leukemia; AML-MRC: AML with myelodysplasia-related changes; CR: complete response; HCT: hematopoietic stem cell transplant; LDAC: low-dose cytarabine; mAb: monoclonal antibody; MDS: myelodysplastic syndromes; OS: overall survival; r/r: relapsed or refractory; t-AML: therapy-related acute myeloid leukemia. 1. Lancet JE et al. 2016 Annual Meeting of the American Society of Clinical Oncology (ASCO 2016). Abstract 7000. 2. Lancet JE et al. 2017 Annual BMT Tandem Meetings (BMT Tandem 2017). Abstract 19. 3. Ravandi F et al. Lancet Oncol. 2015;16:1025‐1036. 4. Ravandi F et al. 58th Annual Meeting of the American Society of Hematology (ASH 2016). Abstract 903. 5. Myelotarg (gemtuzumab ozogamicin) Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761060lbl.pdf. Accessed November 17, 2017. 6. Fathi A et al. ASH 2016. Abstract 591. 7. Jurcic J et al. ASH 2016. Abstract 4050. 8. Pagel JM et al. Blood. 2009;114:5444-5453. Access the activity, “A Master Class on Building Better Therapy for AML: Making the Most of an Increasing Number of Innovative Options,” at www.peerview.com/MJN40.